Uncertainty has a major impact on emotional well-being. Its manifestations within psychiatric disorders are profound and range from the miscalculations of drug abuse to the ruminations of depression. Although most everyone can appreciate that uncertainty causes anxiety in normal individuals, the precise biological mechanisms by which this occurs is not known. Recent political and economic events have made it clear that we live in an unpredictable and uncertain era. The psychological effects of chronic uncertainty are powerful, and the broad aim of this proposal is to understand the neurobiological substrates of uncertainty. Using functional magnetic resonance imaging (fMRI), we propose to elucidate the brain circuitry associated with several aspects of uncertainty. We will use an objective framework for quantifying the amount of uncertainty in a particular circumstance and use several forms of Pavlovian conditioning to measure how uncertainty interacts with the brain's response. In general, we define three aspects of uncertainty: 1) uncertainty for "when"; 2) uncertainty for "what"; and 3) and higher-order (secondary) interactions. We will perform a series of simple classical conditioning experiments on healthy volunteers while they undergo fMRI scanning. We will focus on the activity in the striatal-amygdalar-hippocampal circuit, as these regions have been shown to be necessary for different forms of associative learning. More importantly, the specific roles of these structures in emotional processing are not clear, but our hypothesis is that they code the degree of uncertainty in a context-specific fashion. We will test this hypothesis with a series of 12 fMRI experiments using both pleasant and aversive stimuli. We will use variants of Pavlovian conditioning to associate pleasant oral stimuli (fruit juice) or unpleasant ones (quinine water) with different neutral cues. By varying both the predictability of temporal (when) and stimulus (what) pairings, we will be able to measure how uncertainty modulates the brain's response to this basic learning process. We hypothesize that both the amygdala and ventral striatum will be more active when uncertainty of any form is present. We will further quantify the level of this activation with autonomic measures of arousal. Finally we will investigate how these effects generalize to secondary associations. Ultimately we anticipate that this will suggest new therapies that can be targeted towards the effects of both acute and chronic uncertainty.